Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities

Matthew D Blunt,Stephen G Ward

doi:10.3389/fimmu.2012.00226

Abstract

The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P3 at the D5 position of the inositol ring to create PI(3,4)P2. In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system.

Highlights

Studies using mice in which the genes encoding PI3Kδ or PI3Kγ have been either altered to encode kinase-inactive mutants (e.g., PI3KδD910A mice) or deleted, have revealed that PI3Kδ and PI3Kγ have non-redundant, functions in B cells, T cells, NK cell, neutrophils, mast cells, and dendritic cells (Vanhaesebroeck et al, 2005; Crabbe et al, 2007; Randis et al, 2008; Saudemont et al, 2009; Ward and MarelliBerg, 2009)
SUMMARY The difficulties of developing PI3Kγ inhibitors with sufficient selectivity over other PI3K isoforms has in part, led to the search for alternative drug targets to selectively modify PI3K signaling in the immune system
This search revealed the potential for exploiting the lipid phosphatase SH2 domain-containing inositol-5phosphatase (SHIP)-1, an endogenous and leukocyterestricted regulator of PI3K signaling

Summary

INTRODUCTION

Studies using mice in which the genes encoding PI3Kδ or PI3Kγ have been either altered to encode kinase-inactive mutants (e.g., PI3KδD910A mice) or deleted, have revealed that PI3Kδ and PI3Kγ have non-redundant (but often co-ordinated), functions in B cells, T cells, NK cell, neutrophils, mast cells, and dendritic cells (Vanhaesebroeck et al, 2005; Crabbe et al, 2007; Randis et al, 2008; Saudemont et al, 2009; Ward and MarelliBerg, 2009). While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing This has prompted the search for alternative targets with which to modulate PI3K signaling in the immune system. Calistoga developed CAL-101, a PI3Kδ specific inhibitor that exhibits 40–300-fold selectivity over other PI3K isoforms. CAL-101 displays a dual mechanism of action whereby it both decreases cell survival and reduces chemokine-mediated interactions that retain CLL cells in protective tissue microenvironments (Hoellenriegel et al, 2011; Lannutti et al, 2011). These effects have been observed across a broad www.frontiersin.org

Blunt and Ward

Initiated Completed

Natural killer cells T cell

Findings

PHARMACOLOGICAL MANIPULATION OF SHIP